Use of inhibitors of cyclooxygenase in the treatment of...

Details Use of inhibitors of cyclooxygenase in the treatment of... Use of inhibitors of cyclooxygenase in the treatment of...

2001-02-28

2002-11-26

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S365000, C514S372000, C514S461000, C514S473000, C514S484000

Reexamination Certificate

active

06486194

ABSTRACT:

BACKGROUND TO THE INVENTION
U.S. Pat. No. 5,192,753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors. The non-steroid anti-inflammatory drugs (NSAIDs) referred to in U.S. Pat. No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1). A number of publications have also occurred in the scientific literature which disclose that agents such as acetylacetic acid and indomethecin, which are generally viewed as potent inhibitors of COX-1, can be used in the treatment of Alzheimers disease; see for example:
McGeer et al,
Lancet,
1990:335, 1037;
Rogers et al,
Neurology,
1993:43; 1609-1611;
McGeer et al,
Neurology,
1992:42, 447-449; and
Breitner et al,
Neurology,
1994, 227-232.
Cyclooxygenase (COX) exists in the human as cyclooxygenase type I (COX-I) and cyclooxygenase type II (COX-II also referred to herein as COX-2). Hitherto there has been no suggestion that COX-II plays any role in Alzheimers disease. Indeed there has been no evidence which demonstrates that COX-II plays a part in any human central nervous system disorder. COX-II is inducilible by a number of agents such as mitogen, endotoxin, cytokines and the like but none of these agents which have been demonstrated as inducing COX-II have been shown to be causitive in Alzheimers disease.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
SUMMARY OF INVENTION
The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. Although a wide range of COX-II inhibitors may be employed but it is preferred to employ compounds of the Formula I as set out hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the invention encompasses a method of treating a neurodegenerative disease in a human which comprises administering to said human an effective amount of a non-steroidal COX-2 inhibitor.
Within this apsect the invention encompasses a method of treating the neurodegenerative disease, Alzheimers Disease.
Within the above aspect the invention also encompasses a method of treating stroke, cerebral ischernia and de-myelinating disorders.
Oral administration (such as by tablet or capsule) is a preferred mode of administration
Within the above aspect, there is a preferred classs of method wherein the non-steroidal COX-2 inhibitor will bind at least 100 times as well to COX-2 as to COX-1.
Within the above aspect there is a preferred class of COX-2 inhibitors, which is:
(a) 3-(4-(Aminosulfonyl) phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene,
(b) 3-(4-(Aminosulfonyl) phenyl)-2-(4-fluorophenyl)thiophene,
(c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene,
(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,
(e) 5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl) thiophene-2-carboxylic acid,
(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole,
(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one
(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole,
(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone,
(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl) furan,
(l) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl) thiophene,
(n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene,
(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(p) 5,5-Dimethyl-3-(3fluorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl) phenyl)-2-(5H)-furanone,
(r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone,
(w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone,
(x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone, and
(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
The invention also encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases
or pharmaceutically acceptable salts thereof wherein:
X-Y-Z-is selected from the group consisting of:
(a) —CH
2
CH
2
CH
2
—,
(b) —C(O)CH
2
CH
2
—,
(c) —CH
2
CH
2
C(O)—,
(d) —CR
5
(R
5
′)—O—C(O)—,
(e) —C(O)—O—CR
5
(R
5
′)—,
(f) —CH
2
—NR
3
—CH
2
—,
(g) —CR
5
(R
5
′)—NR
3
—C(O)—,
(h) —CR
4
=CR
4
′—S—,
(i) —S—CR
4
═CR
4
′—,
(j) —S—N═CH—,
(k) —CH⊚N—S—,
(l) —N═CR
4
—O—,
(m) —O—CR
4
═N—
(n) —N═CR
4
—NH—;
(o) —N═CR
4
—S—, and
(p) —S—CR
4
═N—;
(q) —C(O)—NR
3
—CR
5
(R
5
′)—;
(r) —R
3
N—CH═CH— provided R
1
is not —S(O)
2
Me
(s) —CH═CH—NR
3
— provided R
1
is not —S(O)
2
Me
when side b is a double bond, and sides a an c are single bonds; and
X-Y-Z-is selected from the group consisting of:
(a) ═CH—O—CH═, and
(b) ═CH—NR
3
—CH═,
(c) ═N—S—CH═,
(d) ═CH—S—N═,
(e) ═N—O—CH═,
(f) ═CH—O—N═,
(g) ═N—S—N═,
(h) ═N—O—N═,
when sides a and c are double bonds and side b is a single bond;
R
1
is selec

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